HIV clade C (HIV-C) causes >56% of all cases of HIV/AIDS worldwide and predominates in sub-Saharan Africa and India. A non-human primate (NHP) model would greatly benefit the preclinical development of prevention strategies, including drugs, microbicides, and vaccines. Due to host restriction factors, HIV-1 replicates only in humans and chimpanzees, but not in other NHP species. The construction of simian-human immunodeficiency viruses (SHIVs) encoding HIV-1 vpu, tat, rev and env has yielded pathogenic models in rhesus macaques (RMs) or pig-tailed macaques (PMs~ Macaca nemestrina). A primate lentivirus model based mostly upon HIV-1 but replication-competent in macaques would greatly facilitate the preclinical development of new treatment or prevention strategies. Recently, different host restriction factors that block HIV-1 replication in RM cells have been recognized, namely 1) TRIM5?, which targets HIV-1 capsid proteins and blocks early post-entry replication steps, and 2) APOBEC3G (A3G), a cytidine deaminase that is not recognized by HIV-1 Vif and therefore escapes inhibition by this virion-associated protein. Unlike RMs, PMs lack a TRIM5 isoform, which may explain why PMs supported limited acute viremia of unmodified HIV-1 in earlier studies. Replacing HIV-1 vif with that of SIVmac239, SIVmne or HIV-2 has yielded chimeras that replicated for extended periods of time in PMs~ however, these recombinants were based upon the X4-tropic clade B clones, and did not result in persistent viremia and signs of disease progression. We have generated a simian-tropic HIV-C clone, termed stHIV-C, by replacing HIV vif with SIVmac239 vif in an infectious molecular HIV-C clone from Zambia. The chimera is replication-competent in peripheral blood mononuclear cells (PBMC) of M. nemestrina. In a pilot study, the new stHIV-C-vif239 chimera also induced viremia in two PMs~ however, adaptation is incomplete. The Specific Aims are to: 1. Select stHIV-C progeny with improved replication fitness in PMs under prolonged depletion of CD8+ and CD20+ cells~ 2. Further adapt progeny virus by serial passage through immunocompetent PMs, re-isolate virus from the last recipient, generate a large stock, and characterize it in vitro. 3. Perform an intrarectal titration and assess viral pathogenicity 4. Assess the molecular evolution of stHIV-C in the absence and presence of adaptive immunity and during disease progression. We will also compare viral evolution in different compartments (PBMC, lymph nodes, and brain). The proposed experiments are significant because they focus on the development of an NHP model of HIV-C, which predominates in developing countries where the AIDS epidemic continues to escalate and will thus create a new tool for the preclinical development of different strategies for prevention or eradication.